Endobronchial photodynamic therapy (PDT) is a minimally invasive method of palliating major airway obstruction in patients with advanced lung cancer. Initial Phase III trials for FDA approval, which compared Photofrin-PDT with Nd:YAG laser photoresection, found that the duration of palliation was significantly longer after PDT. Effective palliation in these patients is hindered by the prolonged skin photosensitivity associated with Photofrin. 2-[1-hexyloxyethyl]-2-devinyl pyropheophorbide-a (HPPH) is a novel photosensitizer developed at Roswell Park Cancer Institute that is not associated with skin photosensitivity. Phase I experience with this agent has shown it to be safe. We hypothesize that HPPH is a highly effective photosensitizer for palliative PDT of advanced obstructing endobronchial lung cancer without attendant prolonged skin photosensitization. We propose in SA1: To carry out a Phase II study for PDT using HPPH for the treatment of advanced obstructing endobronchial lung cancer. Twenty patients will receive 4 mg/m2 HPPH, followed approximately 48 h later by endoscopic laser light treatment (light dose yet to be determined after completion of Phase l/ll trial), and on Day 5 by endoscopic debridement. Tumor response and symptom relief (cough, dyspnea, hemoptysis) will be determined at Day 5, one month and three months. We have found that covalent crosslinking of non-activated signal transducer and activator of transcription 3 (STAT-3) is a sensitive marker for PDT action because the amount of STAT-3 crosslinks correlates closely with PDT dose and cell survival in vitro and in vivo. We hypothesize that in the future STAT-3 crosslinks may be useful early biomarkers to predict treatment outcome. Occasionally, viable appearing tumor has been observed at the time of clean-out, yet complete tumor response was achieved within months without re-treatment, suggesting that secondary mechanisms, such as vascular, inflammatory and immune responses, may contribute to continued tumor involution. We further hypothesize that secondary delayed effects, such as inflammation, may relate to treatment outcome. We propose in SA2: To explore whether specific primary molecular changes in cells having undergone the above photodynamic exposure can be identified that can serve as early biomarkers of PDT effectiveness. To delineate cellular and molecular changes that may indicate delayed beneficial secondary PDT effects. STAT-3 crosslinks in patient biopsy samples taken before and after PDT will be determined by Western blotting, inflammatory and vascular changes by immunohistochemistry. HPPH level in tissue will be determined by fluorescence analysis. The information gained will also apply to PDT applications other than lung cancer. Lung cancer is the most common cause of cancer death in the Unites States. Research efforts aim to improve survival in these patients, but must continue to care for the rest of the patients who will ultimately succumb to this disease. FDA-approved Photofrin-PDT can ameliorate many of the symptoms related to late-stage disease, but is itself associated with prolonged skin photosensitization. This proposal will be instrumental in the development of a novel PDT drug without long-term restrictions of patients' sun exposure. [unreadable] [unreadable]